Peptoid leads

The design of a peptoid library using non-peptoid leads such as met-enkephalin and morphine represents an important practical instance of a rational... 

If peptide residues are converted to peptoid residues, the conformational heterogeneity of the polymer backbone is likely to increase due to cis/trans isomerization at amide bonds. This will lead to an enhanced loss of conformational entropy upon peptoid/protein association, which could adversely affect binding thermodynamics. A potential solution is the judicious placement of bulky peptoid side chains that constrain backbone dihedral angles. 

Efforts to investigate the questions posed here will lead to more useful peptoid designs while simultaneously leading to a better fundamental understanding of molecular recognition and sequence/structure/function relationships in non-natural, sequence-specific peptidomimetic ohgomers. 

The main objective of this experiment was to demonstrate that a peptide lead compound could be used in rational design of a non-peptide library. One of the natural opiates, met-enkephalin, is used as a hypothetical lead compound. The averaged frequency distribution based on four SA runs is obtained (data not shown). Based on this result, 03 had the highest frequency, and the frequencies of A4, Dll, D13, D14, D16, D2, D3, D5, and D9 are also above random expectation. Apparently, 03 appeared in all the reported active peptoids with opioid activity (cf. Table 1). Comparison of the structure of met-enkephalin (Fig. 5) with 03 indicated that 03 is similar to the side chain of tyrosine, which is the N-terminal residue of met-enkephalin. Among other building blocks found more frequently than random expectation, A4, D3, and D13 are present in the reported opioid peptoids (cf. Table 1). Thus, the SA sampling correctly identified four... 

These examples show how the combinatorial peptoid approach holds enormous potential for the discovery of novel lead structures for drug development. In this context a postmodification on solid-phase of peptoid side chains, bearing alkene and alkyne moieties, via [3 + 2] cyclo-addition of nitrile oxides, enhances further the molecular diversity and the possibility to find new therapeutic agents [11]. Moreover, polymers of N-substituted glycines containing chiral side chains display interesting conformational preferences [12]. NMR and CD data indicate that the major species adopts in methanol a stable right-handed helical structure with o. v-amidc bonds. 

As indicated previously, many pharmacologically interesting target receptors exhibit large surface spanning areas where it has been notoriously difficult to find small molecules as inhibitors. For this purpose peptoids, peptides and especially peptidomimetics derived fixtm structural information of the targets can be valuable tools for lead finding (cf. Chapter 2). 

I SnOaH2 represents a stannic acid molecule on the surface of an ultramicron. As there is no means of deciding between these assumptions and they all lead to the same result, viz the charging of the ultramicrons and the subdivision of the material, it seems easier to abide by assumption one that is the adsorption of the ions by the colloidal particles. The fact that this assumption is the more general, and that it may be employed in explaining the formation of mixed colloids, is a further reason for making it. See Chapter VII on Peptoids. 

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